Although the use of polychlorinated biphenyls (PCBs) and many of the chlorinated pesticides, including DDT, are now prohibited or restricted, there remains concern over their potential human health effects because they persist in the environment, concentrate up the food chain, and are stored in adipose tissue. Laboratory studies show associations of environmentally relevant levels of PCBs and chlorinated pesticides with infertility and pregnancy loss through mechanisms that disrupt embryo development. Epidemiologic studies report associations of PCBs and DDE (stable DDT metabolite) with pregnancy loss. In the proposed study, we will explore the developmental toxicity of chlorinated compounds in women undergoing in vitro fertilization (IVF), which can be used as a model to assess early development, normally unobservable. Developmental endpoints that will be measured include oocyte production, fertilization, and pre- and post-implantation embryo development. Failure at these developmental stages results in infertility and pregnancy loss. Other measured endpoints include clinical pregnancy loss (spontaneous miscarriage and stillbirth) and peri-natal outcomes, such as birth weight. The proposed study is cost-effective because it uses data and specimens from a recently completed NICHD funded multi-center study on epidemiologic predictors of IVF success. In the multi-center study there is data on 2494 couples undergoing 5071 IVF cycles between 1994 and 2003. Serum and ovarian follicular fluid were collected and archived from the female partner and will be used to measure PCBs and chlorinated pesticides such as DDE, hexachlorobenzene, mirex, and the chlordane metabolites, trans-nonachlor and oxychlordane. Subjects completed detailed health and lifestyle questionnaires and information on IVF protocols and pregnancy outcomes were abstracted from patient medical records. The study design is novel because it uses IVF as a model system to study the associations of PCBs and chlorinated pesticides with failure of early development, which manifests clinically as infertility and early pregnancy loss. Early developmental failure represents the majority of losses of pregnancy and is considered the most sensitive developmental stage to PCB and chlorinated pesticide exposure. Since the etiology of infertility and early pregnancy loss remains largely unexplained, the identification of potential environmental risk factors will have large public health significance.